Royal College of Surgeons in Ireland
Association of ultra-rare coding variants with genetic generalized epilepsy.....pdf (1.13 MB)

Association of ultra-rare coding variants with genetic generalized epilepsy: a case–control whole exome sequencing study

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journal contribution
posted on 2023-11-15, 17:35 authored by Mahmoud Koko, Joshua E Motelow, Kate E Stanley, Dheeraj R Bobbili, Ryan S Dhindsa, Patrick May, Canadian Epilepsy Network, Epi4K Consortium, Epilepsy Phenome/Genome Project, EpiPGX Consortium, EuroEPINOMICS-CoGIE Consortium, Gianpiero CavalleriGianpiero Cavalleri, Norman DelantyNorman Delanty

Objective: We aimed to identify genes associated with genetic generalized epilepsy (GGE) by combining large cohorts enriched with individuals with a positive family history. Secondarily, we set out to compare the association of genes independently with familial and sporadic GGE.

Methods: We performed a case-control whole exome sequencing study in unrelated individuals of European descent diagnosed with GGE (previously recruited and sequenced through multiple international collaborations) and ancestry-matched controls. The association of ultra-rare variants (URVs; in 18 834 protein-coding genes) with epilepsy was examined in 1928 individuals with GGE (vs. 8578 controls), then separately in 945 individuals with familial GGE (vs. 8626 controls), and finally in 1005 individuals with sporadic GGE (vs. 8621 controls). We additionally examined the association of URVs with familial and sporadic GGE in two gene sets important for inhibitory signaling (19 genes encoding γ-aminobutyric acid type A [GABAA ] receptors, 113 genes representing the GABAergic pathway).

Results: GABRG2 was associated with GGE (p = 1.8 × 10-5 ), approaching study-wide significance in familial GGE (p = 3.0 × 10-6 ), whereas no gene approached a significant association with sporadic GGE. Deleterious URVs in the most intolerant subgenic regions in genes encoding GABAA receptors were associated with familial GGE (odds ratio [OR] = 3.9, 95% confidence interval [CI] = 1.9-7.8, false discovery rate [FDR]-adjusted p = .0024), whereas their association with sporadic GGE had marginally lower odds (OR = 3.1, 95% CI = 1.3-6.7, FDR-adjusted p = .022). URVs in GABAergic pathway genes were associated with familial GGE (OR = 1.8, 95% CI = 1.3-2.5, FDR-adjusted p = .0024) but not with sporadic GGE (OR = 1.3, 95% CI = .9-1.9, FDR-adjusted p = .19).

Significance: URVs in GABRG2 are likely an important risk factor for familial GGE. The association of gene sets of GABAergic signaling with familial GGE is more prominent than with sporadic GGE.


Research Unit FOR-2715 of the German Research Foundation

National Research Fund of Luxembourg (DFG/FNR grants INTER/DFG/17/11583046 and Le1030/16-1); FNR11264123; INTER/ESF/10/02/CoGIE

‘Stiftung no epilep’

German Academic Exchange Service (DAAD program number 57214224)

National Institutes of Health Grant / Award Number: TL1TR001875, K01MH098126, R01MH099216, R01MH097993, R56AI098588, U01HG007672, R01AG037212 and P01AG007232

FNR funding as part of the National Centre of Excellence in Research on Parkinson’s Disease (NCER-PD, FNR11264123)

Genome Canada and Genome Quebec

National Institute of Neurological Disorders and Stroke Grant / Award Number: U01NS053998, U01NS077274, U01NS077303, U01NS077367 and U01NS077276

European Commission Sixth and Seventh Framework Programs

European Science Foundation through contributing national funding agencies

Open access funding enabled and organized by ProjektDEAL

Epilepsy-Research UK , Grant/Award Number: P1104

Deutsche Forschungsgemeinschaft, Grant/Award Number: Le1030/16-1, Le1030/11-1/2, Nu50/8-1, Sa434/5- 1 and He5415/3-1

Academy of Finland, Grant/Award Number: 141549

Spanish Ministry of Economy and Competitiveness, Grant/Award Number: EUI-EURC-2011- 4325 and SAF2010- 18586

TÜBİTAK, Grant/Award Number: 110S51



The original article is available at

Published Citation

Koko M. et al. Association of ultra-rare coding variants with genetic generalized epilepsy: a case-control whole exome sequencing study. Epilepsia. 2022;63(3):723-735

Publication Date

15 January 2022

PubMed ID



  • Beaumont Hospital
  • School of Pharmacy and Biomolecular Sciences
  • FutureNeuro Centre

Research Area

  • Neurological and Psychiatric Disorders


Blackwell Science


  • Published Version (Version of Record)